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Background: A growing body of epidemiologic and toxicologic literature indicates that fine airborne particulate matter (PM 2.5 ) pollution is neurotoxic and threatens children's neurobehavioral development, resulting in reduced cognitive function. Understanding the magnitude of this effect is critical for establishing public health policies that will protect children's health, preserve human capital, and support societal progress., Objective: To quantify the association between ambient PM 2.5 air pollution and loss of cognitive function in children, as measured by Intelligence Quotient (IQ) scores, through a systematic literature review and meta-analysis., Methods: Following PRISMA guidelines, we conducted a systematic literature search across seven databases: Agricultural and Environmental Science, BIOSIS Citation Index, Embase, GreenFILE, PubMed, Scopus, and Web of Science to identify original scientific studies that investigated the impact of PM 2.5 exposure during pre-and postnatal periods on IQ loss during childhood. Using data from studies included for final review, we conducted a meta-analysis, using a random effects model to compute a beta coefficient that quantifies the overall effect of PM 2.5 exposure on Full-Scale IQ (FSIQ), Performance IQ (PIQ), and Verbal IQ (VIQ)., Findings: Of the 1,107 unique publications identified, six studies met the inclusion criteria for final review, representing 4,860 children across three continents (North America, Europe, and Asia). The mean PM 2.5 concentration across all studies was 30.4 ± 24.4 µg/m 3 . Exposure timing ranged from the prenatal period to mid-childhood. Children were an average of 8.9 years old at the time of cognitive testing. We found that each 1 µg/m 3 increase in PM 2.5 concentration is associated with a -0.27 point change in FSIQ (p < 0.001), 0.39 point change in PIQ (p = 0.003), and -0.24 point change in VIQ (p = 0.021)., Conclusion: Through a systematic review and meta-analysis, we identified a statistically significant relationship between increased exposure to PM 2.5 air pollution and reduced cognitive function in children, with the most pronounced impact on PIQ. This analysis will enable estimation of the burden of adverse neurobehavioral development attributable to PM 2.5 in pediatric populations and will inform local and global strategies for exposure prevention., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Importance: Data are limited on the longitudinal implications of socioeconomic status (SES) for neurodevelopmental outcomes among persons with complex congenital heart disease (CHD)., Objectives: To examine the association of family SES, maternal educational level, and maternal IQ with the neurodevelopment of individuals with dextro-transposition of the great arteries (d-TGA) from age 1 to 16 years and to identify how SES-related disparities change with age., Design, Setting, and Participants: This cohort study analyzed data of participants enrolled in the Boston Circulatory Arrest Study, a randomized clinical trial conducted in Boston, Massachusetts, from 1988 to 1992. Participants were infants with d-TGA who underwent arterial switch operation and, after operation, underwent in-person neurodevelopmental status evaluations at ages 1, 4, 8, and 16 years. Analyses were conducted from April 2021 to August 2024., Exposures: Mean Hollingshead scores at birth, age 1 year, and age 4 years were used to assign participants to SES tertiles (lowest, middle, or highest)., Main Outcomes and Measures: Age-appropriate neurodevelopmental outcomes assessed at 4 study time points (ages 1, 4, 8, and 16 years) via in-person administration of a range of well-validated measures. Standardized neurodevelopmental composite scores from each evaluation were derived from principal component analysis and compared across SES tertiles, adjusting for birth and medical characteristics. These scores were used to categorize the sample into latent classes; patient and medical factors for a 3-class model were used to estimate latent class using multinomial regression., Results: The sample included 164 patients with d-TGA (123 males [75%]; mean [SD] gestational age at birth, 39.8 [1.2] weeks; 3 with Asian [2%], 6 with Black [4%], 5 with Hispanic [3%], and 146 with White [89%] race and ethnicity) and their mothers (mean [SD] age at birth, 28.5 [5.2] years). Lower SES tertile was associated with worse scores on most individual neurodevelopmental tests and worse neurodevelopmental composite scores at ages 4, 8, and 16 years. For example, mean (SD) neurodevelopmental composite scores at age 4 years were -0.49 [0.83] for lowest, 0.00 [0.81] for middle, and 0.47 [1.10] for highest SES tertile (F2 = 15.5; P < .001). When measured at consecutive time points, differences between SES tertiles were of similar magnitude. A latent class analysis produced 2- and 3-class models representing patients with stable (103 [64%] and 85 [53%]), improving (20 [13%]), and declining (57 [36%] and 55 [34%]) neurodevelopmental status. Those experiencing declines in neurodevelopmental status were more likely to have younger maternal age at childbirth (26.6 [5.1] vs 29.6 [4.9] and 29.1 [5.1] years; P = .002), lower maternal IQ (91.0 [14.1] vs 100.1 [11.1] and 96.2 [11.0]; P < .001), and lower SES (35.2 [10.8] vs 40.9 [9.9] and 35.8 [10.1]; P = .003) compared with those with stable or improving status., Conclusions and Relevance: This cohort study of individuals with d-TGA found an association between lower family SES and worse neurodevelopmental outcomes in childhood and continuing throughout adolescence as well as greater decline in neurodevelopmental status over time. Effective strategies are needed to improve access to neurodevelopmental monitoring and intervention services for children with CHD from lower socioeconomic backgrounds.

Background: Environmental chemical exposures in utero may play a role in autism development. While preconception risk factors for autism are increasingly being investigated, little is known about the influence of chemical exposures during the preconception period, particularly for paternal exposures., Methods: In 195 children from the Preconception Environmental exposures And Childhood health Effects (PEACE) cohort born to parents recruited from a fertility clinic in Boston, Massachusetts between 2004 and 2017, we quantified concentrations of 11 phthalate metabolites and bisphenol A (BPA) in urine samples collected from mothers and fathers before conception and mothers throughout pregnancy. When children were 6-15 years old, parents completed the Social Responsiveness Scale (SRS) questionnaire assessing autistic behaviors. We used linear mixed effect models to estimate covariate-adjusted associations of phthalate biomarker and BPA concentrations, separately for maternal preconception (n = 179), paternal preconception (n = 121), and maternal pregnancy (n = 177), with SRS T-scores, based on age and gender, in offspring. We used quantile g-computation models for mixture analyses and evaluated modification by selected dietary factors., Results: The mean SRS T-score was 47.7 (±7.4), lower than the normative mean of 50. In adjusted models for individual biomarkers or mixtures, few associations were observed and estimates were generally negative (e.g., lower SRS T-scores) and imprecise. We observed associations of higher mono-isobutyl phthalate (MiBP) concentrations measured in maternal preconception and paternal preconception periods with lower SRS T-scores (β maternal&#95;precon  = -1.6, 95% CI -2.7; -0.4; β paternal&#95;precon  = -2.9, 95% CI -4.6; -1.2) for each log e increase. In a subset of participants with maternal preconception nutrition information, we generally observed stronger inverse associations with higher folate and iron intake, particularly for folate intake and MiBP concentrations., Conclusions: Urinary phthalate biomarker and BPA concentrations during preconception (maternal and paternal) and pregnancy (maternal) were not associated with adverse autistic behaviors in these children. Larger studies are needed to elucidate the observed associations, while considering interactions between maternal nutrition and chemical exposures., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention (CDC). Use of trade name is for identification only and does not imply endorsement by the CDC, the Public Health Service, or the U.S. Department of Health and Human Services. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Congenital heart disease affects 1% of infants and is associated with impaired neurodevelopment. Right- or left-sided sulcal features correlate with executive function among people with Tetralogy of Fallot or single ventricle congenital heart disease. Studies of multiple congenital heart disease types are needed to understand regional differences. Further, sulcal pattern has not been studied in people with d-transposition of the great arteries. Therefore, we assessed the relationship between sulcal pattern and executive function, general memory, and processing speed in a meta-regression of 247 participants with three congenital heart disease types (114 single ventricle, 92 d-transposition of the great arteries, and 41 Tetralogy of Fallot) and 94 participants without congenital heart disease. Higher right hemisphere sulcal pattern similarity was associated with improved executive function (Pearson r = 0.19, false discovery rate-adjusted P = 0.005), general memory (r = 0.15, false discovery rate P = 0.02), and processing speed (r = 0.17, false discovery rate P = 0.01) scores. These positive associations remained significant in for the d-transposition of the great arteries and Tetralogy of Fallot cohorts only in multivariable linear regression (estimated change β = 0.7, false discovery rate P = 0.004; β = 4.1, false discovery rate P = 0.03; and β = 5.4, false discovery rate P = 0.003, respectively). Duration of deep hypothermic circulatory arrest was also associated with outcomes in the multivariate model and regression tree analysis. This suggests that sulcal pattern may provide an early biomarker for prediction of later neurocognitive challenges among people with congenital heart disease., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Epidemiologic studies on health effects of parental preconception exposures are limited despite emerging evidence from toxicological studies suggesting that such exposures, including to environmental chemicals, may affect offspring health., Objective: We investigated whether maternal and paternal preconception and maternal pregnancy urinary phthalate metabolite and bisphenol A (BPA) concentrations were associated with child behavior., Methods: We analyzed data from the Preconception Environmental exposure And Childhood health Effects (PEACE) Study, an ongoing prospective cohort study of children aged 6-11 years whose parent(s) previously enrolled in the prospective preconception Environment and Reproductive Health (EARTH) study. Using linear mixed models, we estimated covariate-adjusted associations of 11 urinary phthalate metabolite and BPA concentrations collected prior to conception and during pregnancy with Behavioral Assessment System for Children-3 (BASC-3) T-scores (higher scores indicate more problem behaviors)., Results: This analysis included 134 mothers, 87 fathers and 157 children (24 sets of twins); parents were predominantly non-Hispanic white (mothers and fathers86%). Higher maternal preconception or pregnancy monobenzyl phthalate (MBzP) concentrations were related to higher mean externalizing problems T-scores in their children (β = 1.3 per 1-log e unit increase; 95 % CI: -0.2, 2.4 and β = 2.1, 95 % CI: 0.7, 3.6, respectively). Higher maternal preconception monocarboxyoctyl phthalate (MCOP) was suggested to be related to lower mean externalizing problems T-scores (β = -0.9; 95 % CI: -1.8, 0.0). Higher paternal preconception MCOP was suggestively associated with lower internalizing problems (β = -0.9; 95 %CI:-1.9, 0.1) and lower Behavioral Symptoms Index (BSI) T-scores (β = -1.3; 95 % CI: -2.1, -0.4)., Conclusion: In this cohort, higher maternal preconception and pregnancy MBzP were associated with worse parent-reported child behavior, while higher maternal and paternal preconception MCOP concentrations were related to lower BASC-3 scores., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Epidemiologic studies of the effects of parental preconception paraben exposures on child behavior are limited despite emerging evidence suggesting that such exposures may affect offspring neurodevelopment., Objective: We investigated whether maternal and paternal preconception and maternal pregnancy urinary concentrations of parabens were associated with child behavior., Methods: We analyzed data from the Preconception Environmental exposure And Childhood health Effects Study, an ongoing prospective cohort of children aged 6-13 years and their parents. We estimated covariate-adjusted associations of log e -transformed urinary methyl, propyl, and butyl paraben concentrations (individually using linear regression models and as a mixture using quantile g-computation) collected prior to conception and during pregnancy with Behavioral Assessment System for Children-3 and Behavior Rating Inventory of Executive Function T-scores (higher scores indicate more problem behaviors)., Results: This analysis included 140 mothers, 81 fathers, and 171 children (25 sets of twins); parents were predominantly non-Hispanic white (88% for both mothers and fathers). In single paraben models, higher paternal preconception urinary propyl and methyl paraben concentrations were associated with higher Internalizing Problem T-scores (propyl paraben β $\beta \;$ = 1.7; 95% confidence interval: 0.6, 2.8, methyl paraben β $\beta \;$ = 2.2; 95% confidence interval: 0.5, 3.9) and higher Behavioral Symptom Index T-scores (propyl paraben β $\beta \;$ = 1.4; 95% confidence interval: 0.3, 2.5, methyl paraben β $\beta \;$ = 1.6; 95% confidence interval: -0.1, 3.3). Each quantile increase in the paternal mixture of three parabens was associated with a 3.4 (95% confidence interval: 0.67, 6.1) and 2.5 (95% confidence interval: 0.01, 5.0) increased internalizing problem and Behavioral Symptom Index T-scores respectively. Higher paternal preconception ( β $\beta \;$ = 1.0; 95% confidence interval: 0.04, 1.9) and maternal preconception ( β $\beta \;$ = 1.1 95% confidence interval: -0.1, 2.2) concentrations of propyl paraben were associated with higher Behavior Rating Inventory of Executive Function Metacognition Index T-scores in children, but the paraben mixtures was not., Conclusion: In this cohort, paternal preconception urinary concentrations of propyl and methyl paraben were associated with worse parent-reported child behaviors., (© 2023 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)

Autism spectrum disorders are more prevalent in children with congenital heart disease (CHD) than in the general population. Children with CHD without diagnosed autism are also at increased risk for neurodevelopmental and psychiatric impairments. We characterized social and behavioral outcomes in children with CHD and examined neurodevelopmental and psychiatric comorbidities. Children without diagnosed autism who underwent infant open-heart surgery were eligible. Parent-reports assessed social communication, unusual behaviors, self-regulation, anxiety, and executive function (EF). Neuropsychological tests assessing theory of mind (ToM), working memory, and verbal comprehension were administered. Outcomes were compared to normative data. Linear regressions were estimated with parent-reported scores and ToM abilities as outcomes. Predictors were anxiety symptoms, parent-reported EF, and working memory scores. Covariates were age, parental education, ADHD diagnosis, and verbal comprehension. Clinically relevant comorbidities were identified ( N children scoring ≥1 SD below the norm). Fifty-six children (10.8 ± 1.8 years) participated virtually. Compared to norms, children with CHD had impaired ToM, more unusual behaviors ( p = .002), and less self-regulation ( p  = .018), but better social communication ( p  = .014). "Autism-like" traits were positively associated with anxiety symptoms ( ß (95% CI) = 0.28(0.08-0.49), p  = .008) and worse working memory ( ß (95% CI) = -0.36(-0.59-0.13), p  = .003). Twenty-one out of 22 children who displayed clinically relevant social and behavioral scores also showed anxiety symptoms ( n  = 4), impaired EF ( n  = 7), or both ( n  = 10). Children with CHD without diagnosed autism have elevated unusual behaviors, lower self-regulation, and impaired ToM. There is a high risk of co-existing anxiety and impaired EF which may increase disease burden. Targeted therapeutic interventions are needed to reduce long-term psychosocial risks in these children. Abbreviation Attention deficit/hyperactivity disorder (ADHD), Autism Spectrum Rating Scale (ASRS), Behavior Rating Inventory of Executive Functions for school-aged children, 2nd Edition (BRIEF-2), cardiopulmonary bypass (CPB), congenital heart disease (CHD), Empathy/Systematizing Quotient Child Version (ESQ-C), Multidimensional Anxiety Scale for Children, 2nd Edition (MASC-2), Social Responsiveness Scale (School-age form), 2nd Edition (SRS-2), theory of mind (ToM), Theory of Mind Task Battery (ToM-TB), Wechsler Intelligence Scale for Children, 5th edition (WISC-V).

Background: Studies of prenatal air pollution (AP) exposure on child neurodevelopment have mostly focused on a single pollutant. We leveraged daily exposure data and implemented novel data-driven statistical approaches to assess effects of prenatal exposure to a mixture of seven air pollutants on cognitive functioning in school-age children from an urban pregnancy cohort., Methods: Analyses included 236 children born at ≥37 weeks gestation. Maternal prenatal daily exposure levels for nitrogen dioxide (NO 2 ), ozone (O 3 ), and constituents of fine particles [elemental carbon (EC), organic carbon (OC), nitrate (NO 3 - ), sulfate (SO 4 2- ), ammonium (NH 4 + )] were estimated based on residential addresses using validated satellite-based hybrid models or global 3-D chemical-transport models. Children completed Wide Range Assessment of Memory and Learning (WRAML-2) and Conners' Continuous Performance Test (CPT-II) at 6.5 ± 0.9 years of age. Time-weighted levels for mixture pollutants were estimated using Bayesian Kernel Machine Regression Distributed Lag Models (BKMR-DLMs), with which we also explored the interactions in the exposure-response functions among pollutants. Resulting time-weighted exposure levels were used in Weighted Quantile Sum (WQS) regressions to examine AP mixture effects on outcomes, adjusted for maternal age, education, child sex, and prenatal temperature., Results: Mothers were primarily ethnic minorities (81% Hispanic and/or black) reporting ≤12 years of education (68%). Prenatal AP mixture (per unit increase in WQS estimated AP index) was associated with decreased WRAML-2 general memory (GM; β = -0.64, 95%CI = -1.40, 0.00) and memory-related attention/concentration (AC; β = -1.03, 95%CI = -1.78, -0.27) indices, indicating poorer memory functioning, as well as increased CPT-II omission errors (OE; β = 1.55, 95%CI = 0.34, 2.77), indicating increased attention problems. When stratified by sex, association with AC index was significant among girls, while association with OE was significant among boys. Traffic-related pollutants (NO 2 , OC, EC) and SO 4 2- were major contributors to these associations. There was no significant evidence of interactions among mixture components., Conclusions: Prenatal exposure to an AP mixture was associated with child neurocognitive outcomes in a sex- and domain-specific manner., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Dramatic advances in the management of congenital heart disease (CHD) have improved survival to adulthood from less than 10% in the 1960s to over 90% in the current era, such that adult CHD (ACHD) patients now outnumber their pediatric counterparts. ACHD patients demonstrate domain-specific neurocognitive deficits associated with reduced quality of life that include deficits in educational attainment and social interaction. Our hypothesis is that ACHD patients exhibit vascular brain injury and structural/physiological brain alterations that are predictive of specific neurocognitive deficits modified by behavioral and environmental enrichment proxies of cognitive reserve (e.g., level of education and lifestyle/social habits). This technical note describes an ancillary study to the National Heart, Lung, and Blood Institute (NHLBI)-funded Pediatric Heart Network (PHN) "Multi-Institutional Neurocognitive Discovery Study (MINDS) in Adult Congenital Heart Disease (ACHD)". Leveraging clinical, neuropsychological, and biospecimen data from the parent study, our study will provide structural-physiological correlates of neurocognitive outcomes, representing the first multi-center neuroimaging initiative to be performed in ACHD patients. Limitations of the study include recruitment challenges inherent to an ancillary study, implantable cardiac devices, and harmonization of neuroimaging biomarkers. Results from this research will help shape the care of ACHD patients and further our understanding of the interplay between brain injury and cognitive reserve.

Background: Air pollution exposure during pregnancy affects children's brain function. Maternal stress and nutrition, socioeconomic status, and the child's sex may modify this relationship., Objective: To identify characteristics of children with the largest increases in full-scale IQ (FSIQ) after their mothers used HEPA filter air cleaners during pregnancy., Methods: In this randomized controlled trial we randomly assigned women to receive 1-2 air cleaners or no air cleaners during pregnancy. We analyzed maternal hair samples for cortisol and dehydroepiandrosterone (DHEA). When the children were 48 months old, we measured FSIQ with the Wechsler Preschool and Primary Scale of Intelligence. We evaluated ten potential modifiers of the intervention-FSIQ relationship using interaction terms in separate regression models. To account for correlations between modifiers, we also used a single regression model containing main effects and intervention x modifier terms for all potential modifiers., Results: Among 242 mother-child dyads with complete data, the intervention was associated with a 2.3-point increase (95% CI: -1.5, 6.0 points) in mean FSIQ. The intervention improved mean FSIQ among children of mothers in the bottom (5.4 points; 95% CI: -0.8, 11.5) and top (6.1 points; 95% CI: 0.5, 11.8) cortisol tertiles, but not among those whose mothers were in the middle tertile. The largest between-group difference in the intervention's effect was a 7.5-point (95% CI: -0.7, 15.7) larger increase in mean FSIQ among children whose mothers did not take vitamins than among children whose mothers did take vitamins (interaction p-value = 0.07). We also observed larger benefits among children whose mothers did not complete university, and those with lower hair DHEA concentrations, hair cortisol concentrations outside the middle tertile, or more perceived stress., Conclusion: The benefits of reducing air pollution during pregnancy on brain development may be greatest for children whose mothers who do not take vitamins, experience more stress, or have less education., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The HEPA filter air cleaners used in this study were purchased at a discounted rate from the manufacturer, who also made minor modifications to the air cleaners at our request. The authors have no other conflicts of interest to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: High-level prenatal and childhood arsenic (As) exposure characteristic of several regions in Asia (e.g., Bangladesh), may impact motor function. However, the relationship between lower-level arsenic exposure (characteristic of other regions) and motor development is largely unstudied, despite the potential for deficient motor skills in childhood to have adverse long-term consequences. Thus, we sought to investigate the association between prenatal As exposure and motor function among 395 children in the New Hampshire Birth Cohort Study, a rural cohort from northern New England., Methods: Prenatal exposure was estimated by measuring maternal urine speciated As at 24-28 weeks of gestation using high-performance liquid chromatography (HPLC) inductively coupled plasma mass spectrometry (ICP-MS) and summing inorganic As, monomethylarsonic acid, and dimethylarsinic acid to obtain total urinary As (tAs). Motor function was assessed with the Bruininks-Oseretsky Test of Motor Proficiency, 2nd Edition (BOT-2) at a mean (SD) age of 5.5 (0.4) years., Results: Children who completed this exam were largely reported as white race (97%), born to married mothers (86%) with a college degree or higher (67%). The median (IQR) gestational urine tAs concentration was 4.0 (5.0) µg/L. Mean (SD) BOT-2 scores were 48.6 (8.4) for overall motor proficiency and 48.2 (9.6) for fine manual control [standard score = 50 (10)], and were 16.3 (5.1) for fine motor integration and 12.5 (4.1) for fine motor precision [standard score = 15 (5)]. We found evidence of a non-linear dose response relationship and used a change-point model to assess the association of tAs with overall motor proficiency and indices of fine motor integration, fine motor precision, and their composite, fine manual control, adjusted for age and sex. In models adjusted for potential confounders, each doubling of urine tAs decreased overall motor proficiency by -3.3 points (95% CI: -6.1, -0.4) for tAs concentrations greater than the change point of 9.5 µg/L and decreased fine motor integration by -4.3 points (95% CI: -8.0, -0.6) for tAs concentrations greater than the change point of 17.0 µg/L., Discussion: In summary, we found that levels of prenatal As exposure above an empirically-derived threshold (i.e., the change point) were associated with decrements in childhood motor development in a US population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Butler, Karagas, Demidenko, Bellinger and Korrick.)

Patients with hypoplastic left heart syndrome who have been palliated with the Fontan procedure are at risk for adverse neurodevelopmental outcomes, lower quality of life, and reduced employability. We describe the methods (including quality assurance and quality control protocols) and challenges of a multi-center observational ancillary study, SVRIII (Single Ventricle Reconstruction Trial) Brain Connectome. Our original goal was to obtain advanced neuroimaging (Diffusion Tensor Imaging and Resting-BOLD) in 140 SVR III participants and 100 healthy controls for brain connectome analyses. Linear regression and mediation statistical methods will be used to analyze associations of brain connectome measures with neurocognitive measures and clinical risk factors. Initial recruitment challenges occurred that were related to difficulties with: (1) coordinating brain MRI for participants already undergoing extensive testing in the parent study, and (2) recruiting healthy control subjects. The COVID-19 pandemic negatively affected enrollment late in the study. Enrollment challenges were addressed by: (1) adding additional study sites, (2) increasing the frequency of meetings with site coordinators, and (3) developing additional healthy control recruitment strategies, including using research registries and advertising the study to community-based groups. Technical challenges that emerged early in the study were related to the acquisition, harmonization, and transfer of neuroimages. These hurdles were successfully overcome with protocol modifications and frequent site visits that involved human and synthetic phantoms.

Importance: Neurodevelopmental disabilities are commonly associated with congenital heart disease (CHD), but medical and sociodemographic factors explain only one-third of the variance in outcomes., Objective: To examine whether potentially damaging de novo variants (dDNVs) in genes not previously linked to neurodevelopmental disability are associated with neurologic outcomes in CHD and, post hoc, whether some dDNVs or rare putative loss-of-function variants (pLOFs) in specific gene categories are associated with outcomes., Design, Setting, and Participants: This cross-sectional study was conducted from September 2017 to June 2020 in 8 US centers. Inclusion criteria were CHD, age 8 years or older, and available exome sequencing data. Individuals with pathogenic gene variants in known CHD- or neurodevelopment-related genes were excluded. Cases and controls were frequency-matched for CHD class, age group, and sex., Exposures: Heterozygous for (cases) or lacking (controls) dDNVs in genes not previously associated with neurodevelopmental disability. Participants were separately stratified as heterozygous or not heterozygous for dDNVs and/or pLOFs in 4 gene categories: chromatin modifying, constrained, high level of brain expression, and neurodevelopmental risk., Main Outcomes and Measures: Main outcomes were neurodevelopmental assessments of academic achievement, intelligence, fine motor skills, executive function, attention, memory, social cognition, language, adaptive functioning, and anxiety and depression, as well as 7 structural, diffusion, and functional brain magnetic resonance imaging metrics., Results: The study cohort included 221 participants in the post hoc analysis and 219 in the case-control analysis (109 cases [49.8%] and 110 controls [50.2%]). Of those 219 participants (median age, 15.0 years [IQR, 10.0-21.2 years]), 120 (54.8%) were male. Cases and controls had similar primary outcomes (reading composite, spelling, and math computation on the Wide Range Achievement Test, Fourth Edition) and secondary outcomes. dDNVs and/or pLOFs in chromatin-modifying genes were associated with lower mean (SD) verbal comprehension index scores (91.4 [20.4] vs 103.4 [17.8]; P = .01), Social Responsiveness Scale, Second Edition, scores (57.3 [17.2] vs 49.4 [11.2]; P = .03), and Wechsler Adult Intelligence Scale, Fourth Edition, working memory scores (73.8 [16.4] vs 97.2 [15.7]; P = .03), as well as higher likelihood of autism spectrum disorder (28.6% vs 5.2%; P = .01). dDNVs and/or pLOFs in constrained genes were associated with lower mean (SD) scores on the Wide Range Assessment of Memory and Learning, Second Edition (immediate story memory: 9.7 [3.7] vs 10.7 [3.0]; P = .03; immediate picture memory: 7.8 [3.1] vs 9.0 [2.9]; P = .008). Adults with dDNVs and/or pLOFs in genes with a high level of brain expression had greater Conners adult attention-deficit hyperactivity disorder rating scale scores (mean [SD], 55.5 [15.4] vs 46.6 [12.3]; P = .007)., Conclusions and Relevance: The study findings suggest neurodevelopmental outcomes are not associated with dDNVs as a group but may be worse in individuals with dDNVs and/or pLOFs in some gene sets, such as chromatin-modifying genes. Future studies should confirm the importance of specific gene variants to brain function and structure.

Elevated exposure to multiple trace metals can be neurotoxic even at relatively low levels. These findings are primarily evident from adult occupational studies as well as in children exposed prenatally or in early childhood. Less research has focused on the neurodevelopmental impacts of exposure to metals among school-aged children. We examined associations between exposure to a mixture of four metals (arsenic, cadmium, manganese, lead) measured in hair and markers of cognition, attention, and behavior among 222 6-12 year old children who participated in a 2009-2010 neurodevelopmental follow-up to the C8 Health Project. Using quantile-based g-computation we estimated the adjusted overall metal mixture effect ψ (95 % CI) as the change in outcome per decile increase in all metals in the mixture. Hair metal levels varied by metal, with cadmium being lowest (median 0.007, interquartile range (IQR) 0.013 μg/g) and lead the highest concentration (median 0.152, IQR 0.252 μg/g). Children's cognitive skills and development, attention/impulsivity, and behavior were all close to standardized population means. Each decile increase in all metals was associated with a Full Scale IQ reduction of 1.01 points (95 % confidence interval (CI) -1.88, -0.15) and Verbal IQ reduction of 1.11 points (95 % CI -1.97, -0.25), adjusted for child age, sex, secondhand smoke exposure, HOME score, maternal education, maternal IQ, and examiner. Maternal report of ADHD-like behaviors and executive functioning also showed adverse associations with the metal mixture. Our findings suggest that similar to exposure during prenatal and early childhood periods, recent exposure to metals during middle childhood is associated with adverse neurodevelopmental consequences. Middle childhood may also be a developmental window of susceptibility to the negative consequences of exposure to environmental neurotoxicants., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Cheryl R Stein reports financial support was provided by National Institutes of Health. Mary S Wolff reports financial support was provided by National Institutes of Health. David A Savitz reports financial support was provided by Garden City Group. David A Savitz reports a relationship with Attorneys that includes: paid expert testimony., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Children with congenital heart defects have an increased risk of neurodevelopmental disability. The impact of environmental chemical exposures during daily life on neurodevelopmental outcomes in toddlers with congenital heart defects is unknown., Methods: This prospective study investigated the impacts of early childhood exposure to mixtures of environmental chemicals on neurodevelopmental outcomes after cardiac surgery. Outcomes were assessed at 18 months of age using The Bayley Scales of Infant and Toddler Development-III. Urinary concentrations of exposure biomarkers of pesticides, phenols, parabens, and phthalates, and blood levels of lead, mercury, and nicotine were measured at the same time point. Bayesian profile regression and weighted quantile sum regression were utilized to assess associations between mixtures of biomarkers and neurodevelopmental scores., Results: One-hundred and forty infants were enrolled, and 110 (79%) returned at 18 months of age. Six biomarker exposure clusters were identified from the Bayesian profile regression analysis; and the pattern was driven by 15 of the 30 biomarkers, most notably 13 phthalate biomarkers. Children in the highest exposure cluster had significantly lower adjusted language scores by -9.41 points (95%CI: -17.2, -1.7) and adjusted motor scores by -4.9 points (-9.5, -0.4) compared to the lowest exposure. Weighted quantile sum regression modeling for the overall exposure-response relationship showed a significantly lower adjusted motor score (β = -2.8 points [2.5th and 97.5th percentile: -6.0, -0.6]). The weighted quantile sum regression index weights for several phthalates, one paraben, and one phenol suggest their relevance for poorer neurodevelopmental outcomes., Conclusions: Like other children, infants with congenital heart defects are exposed to complex mixtures of environmental chemicals in daily life. Higher exposure biomarker concentrations were associated with significantly worse performance for language and motor skills in this population., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background: Developmental exposure to airborne particulate matter (PM) may increase children's risk of developing autism spectrum disorder. We quantified the impact of reducing PM exposure during pregnancy on the development of autistic traits in children. We also assessed associations between indoor fine PM (PM 2.5 ) concentrations during pregnancy and autistic traits., Methods: In this parallel-group randomized controlled trial, we randomized 540 non-smoking pregnant women to receive HEPA filter air cleaners or to a control group, which did not receive air cleaners. We administered the Social Responsiveness Scale (SRS-2) to caregivers when children were a median of 48 months (range: 48 to 51 months). Our primary outcome was the SRS-2 total T-score. We imputed missing data using multiple imputation with chained equations and our primary analysis was by intention to treat. In secondary analyses, we estimated associations between full pregnancy and trimester-specific indoor PM 2.5 concentrations and T-scores., Results: We enrolled participants at a median of 11 weeks' gestation. Our analysis included 478 children (233 control, 245 intervention). The intervention reduced average indoor PM 2.5 concentrations by 29 % (95 % CI: 21, 37 %). The mean SRS-2 total T-score was 0.5 units lower (95 % CI: -2.5, 1.5) among intervention participants, with evidence of larger benefits for children at the high end of the T-score distribution. An interquartile range (9.6 µg/m 3 ) increase in indoor PM 2.5 during pregnancy was associated with 1.8-unit (95 % CI: 0.3, 3.2) increase in mean SRS-2 total T-score. Effect estimates for PM 2.5 concentrations by trimester were smaller and confidence intervals spanned no effect., Conclusion: Reducing indoor PM during pregnancy had little impact on mean autism-related behavior scores in children. However, indoor PM 2.5 concentrations during pregnancy were associated with higher scores. Exposure to particulate matter during pregnancy may influence the development of autistic traits in childhood., Trial Registration: ClinicalTrials.gov: NCT01741051., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Problem-solving skills build upon three core executive functions: inhibition, working memory, and cognitive flexibility. There is evidence of adverse associations of prenatal exposure to manganese (Mn) with core executive functions, but less is known about Mn associations with problem-solving or potential mediators of this association., Objectives: This study aimed to investigate the association of prenatal Mn exposure with problem-solving and to identify potential neuropsychological mechanisms through which this association may be mediated., Methods: Study participants were 410 adolescents from the New Bedford Cohort (NBC) who have undergone periodic evaluations since their birth (1993-1998) to mothers residing near a Massachusetts Superfund site. We investigated the association of cord blood Mn with problem-solving measured by the Delis-Kaplan Executive Function System (D-KEFS) Sorting and Tower subtests (scores scaled to a mean ± SD of 10 ± 3) using multivariable linear regression. Inhibition and cognitive flexibility were also measured by the D-KEFS; working memory was measured with the Wide Range Assessment of Memory and Learning, 2nd edition. Regression-based causal mediation analysis was used to assess the proportion of the Mn-problem-solving association mediated by inhibition, working memory, and cognitive flexibility individually and jointly., Results: NBC adolescents (mean age 15.5 years) were socio-demographically diverse with 31 % in a low-income household at birth and had cord blood Mn concentrations similar to other general population samples. Mn was associated with Sorting but not Tower scores. Specifically, a doubling of cord blood Mn concentrations was associated with - 0.59 points lower (95 % CI: -1.16, -0.03) Sort Recognition score. In mediation analyses, there was suggestive evidence that inhibition, working memory, and cognitive flexibility combined mediated 30 % of the total effect of Mn on Sorting. When analyzed individually, working memory mediated a larger proportion (24 %) of the effect than inhibition or cognitive flexibility., Discussion: We observed adverse associations of cord blood Mn with problem-solving among adolescents. There was suggestive evidence that the building blocks of executive function jointly, and working memory individually, were potentially important mediators of this association., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose of Review: Nearly 100 clinical studies have been published evaluating neurodevelopmental outcomes in children following surgery and anesthesia. These studies have reported mixed results, likely attributable at least in part to significant heterogeneity in their study designs, types and numbers of exposures, patient populations evaluated, and most importantly, the outcomes that were assessed. This review aims to summarize the results from clinical studies evaluating behavioral outcomes in children exposed to surgery and anesthesia., Recent Findings: Children with early exposure to surgery and anesthesia were found to have limited to no differences in intelligence when compared with unexposed children. However, several studies have reported more behavioral problems in children exposed to general anesthesia. An increased incidence of attention-deficit hyperactivity disorder has also been reported in anesthetic exposed children, particularly after multiple exposures., Summary: Nearly all clinical studies of anesthetic neurotoxicity are observational in nature, so the associations between anesthetic exposure and behavioral deficits cannot yet be directly attributed to the anesthetic medication. However, the finding of deficits in some neurodevelopmental domains and not others will help guide the selection of appropriate outcomes in future studies of anesthetic neurotoxicity that can further evaluate whether anesthetic medications have an impact on neurodevelopment in children., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: A link between the gut microbiome and behavior is hypothesized, but most previous studies are cross-sectional or in animal models. The modifying role of host sex is poorly characterized. We aimed to identify sex-specific prospective associations between the early-life gut microbiome and preschool-age neurobehavior., Methods: In a prospective cohort, gut microbiome diversity and taxa were estimated with 16S rRNA sequencing at 6 weeks, 1 year, and 2 years. Species and gene pathways were inferred from metagenomic sequencing at 6 weeks and 1 year. When subjects were 3 years old, parents completed the Behavioral Assessment System for Children, second edition (BASC-2). A total of 260 children contributed 523 16S rRNA and 234 metagenomics samples to analysis. Models adjusted for sociodemographic characteristics., Results: Higher diversity at 6 weeks was associated with better internalizing problems among boys, but not girls [β Boys  = -1.86 points/SD Shannon diversity; 95% CI (-3.29, -0.42), p Boys  = 0.01, β Girls  = 0.22 (-1.43, 1.87), p Girls  = 0.8, p interaction  = 0.06]. Among other taxa-specific associations, Bifidobacterium at 6 weeks was associated with Adaptive Skills scores in a sex-specific manner. We observed relationships between functional features and BASC-2 scores, including vitamin B6 biosynthesis pathways and better Depression scores., Conclusions: This study advances our understanding of microbe-host interactions with implications for childhood behavioral health., Impact: This is one of the first studies to examine the early-life microbiome and neurobehavior, and the first to examine prospective sex-specific associations. Infant and early-childhood microbiomes relate to neurobehavior including anxiety, depression, hyperactivity, and social behaviors in a time- and sex-specific manner. Our findings suggest future studies should evaluate whether host sex impacts the relationship between the gut microbiome and behavioral health outcomes., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Objective: To identify predictors of impaired executive function in adolescents after surgical repair of critical congenital heart disease (CHD)., Study Design: We analyzed patient factors, medical and surgical history, and family social class from 3 single-center studies of adolescents with d-transposition of the great arteries (d-TGA), tetralogy of Fallot (TOF), and Fontan repair. Machine learning models were developed using recursive partitioning to predict an executive function composite score based on five subtests (population mean 10, SD 3) of the Delis-Kaplan Executive Function System., Results: The sample included 386 patients (139 d-TGA, 91 TOF, 156 Fontan) of age 15.1 ± 2.1 (mean ± SD) years and an executive function composite score of 8.6 ± 2.4. Family social class emerged as the most important predictive factor. The lowest (worst) mean executive function score (5.3) occurred in patients with low to medium social class (Hollingshead index <56) with one or more neurologic events and a diagnosis of TOF. The highest (best) mean score (9.7) occurred in subjects with high social class (Hollingshead index ≥56) and shorter duration of deep hypothermic circulatory arrest. Other factors predicting lower executive function scores included low birth weight and a greater number of catheterizations., Conclusions: In regression tree modeling, family social class was the strongest predictor of executive function in adolescents with critical CHD, even in the presence of medical risk factors. Additional predictors included CHD diagnosis, birth weight, neurologic events, and number of procedures. These data highlight the importance of social class in mitigating risks of executive dysfunction in CHD., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Developmental exposure to air pollution is associated with diminished cognitive abilities in observational studies, but no randomized controlled trial has examined the effect of reducing air pollution on cognition in children., Objectives: We sought to quantify the impact of reducing exposure to particulate matter (PM) during pregnancy on children's cognitive performance at 4 y of age., Methods: In this single-blind, parallel-group, randomized controlled trial in Ulaanbaatar, Mongolia, we randomly assigned 540 nonsmoking pregnant women (268 intervention and 272 control) to receive 1-2 portable high-efficiency particulate air (HEPA) filter air cleaners or no air cleaners. The air cleaners were used from a median of 11 wk gestation until the end of pregnancy. The primary outcome was full-scale intelligence quotient (FSIQ) assessed using the Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV) when children were a median of 48 months old. We imputed missing outcome data using multiple imputation with chained equations, and our primary analysis was by intention to treat., Results: After excluding known miscarriages, stillbirths, neonatal deaths, and medical conditions that impeded cognitive testing and imputation, 475 (233 control and 242 intervention) children were included in our analyses. In an unadjusted analysis, the mean FSIQ of children who were randomly assigned to the intervention group was 2.5 points [95% confidence interval (CI): - 0.4 , 5.4 points] higher than that of children in the control group. After adjustment to account for an imbalance in preterm birth between groups, the effect estimate increased to 2.8 points (95% CI: - 0.1 , 5.7)., Conclusions: Reducing PM air pollution during pregnancy may improve cognitive performance in childhood. https://doi.org/10.1289/EHP10302.

Background: Although prenatal chemical exposures influence neurobehavior, joint exposures are not well explored as risk factors for internalizing disorders through adolescence., Objective: To evaluate associations of prenatal organochlorine and metal exposures, considered individually and as a mixture, with mid-childhood and adolescent internalizing symptoms., Methods: Participants were 468 children from a prospective cohort recruited at birth (1993-1998) in New Bedford, Massachusetts. Organochlorines (hexachlorobenzene, p,p'-dichlorodiphenyl dichloroethylene, polychlorinated biphenyls) and metals (lead, manganese) were analyzed in cord blood. Internalizing symptoms (anxiety, depressive, somatic) were assessed via multiple informants on the Conners' Rating Scale (CRS) at 8-years and Behavior Assessment System for Children, Second Edition (BASC-2) at 15-years; higher T-scores indicate greater symptoms. Overall and sex-specific covariate-adjusted associations were evaluated using Bayesian Kernel Machine Regression (BKMR) and five-chemical linear regression models., Results: The cohort was socioeconomically diverse (35% household income <$20,000; 55% maternal ≤ high school education at birth). Most chemical concentrations were consistent with background levels [e.g., median (range) cord blood lead: 1.1 (0-9.4) μg/dL]. BKMR suggested linear associations and no interactions between chemicals. The overall mixture was positively associated with Conners' Parent Rating Scale (CPRS) and BASC-2 Self Report of Personality (SRP) anxiety and depressive symptoms, and negatively with somatic symptoms. Prenatal lead was positively associated with adolescent anxiety symptoms [1.56 (95% CI: 0.50, 2.61) BASC-2 SRP Anxiety score increase per doubling lead]. For CRPS and BASC-2 SRP, a doubling of cord blood manganese was positively associated with internalizing symptoms for girls [e.g., 3.26 (95% CI: 0.27, 6.25) BASC-2 SRP Depression score increase], but not boys. Organochlorine exposures were not adversely associated with internalizing symptoms., Discussion: Low-level prenatal lead exposure was positively associated with adolescent anxiety symptoms, and prenatal manganese exposure was positively associated with internalizing symptoms for girls from mid-childhood through adolescence. In utero neurotoxicant metal exposures may contribute to the emergence of anxiety and depression., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Working memory is the ability to keep information in one's mind and mentally manipulate it. Decrements in working memory play a key role in many behavioral and psychiatric disorders, therefore identifying modifiable environmental risk factors for such decrements is important for mitigating these disorders. There is some evidence that prenatal exposure to individual chemicals may adversely impact working memory among children, but few studies have explored the association of co-exposure to multiple chemicals with this outcome in adolescence, a time when working memory skills undergo substantial development. We investigated the association of organochlorines (DDE, HCB, PCBs) and metals (lead, manganese) measured in cord serum and cord blood, respectively, with working memory measured with the Wide Range Assessment of Memory and Learning, 2nd Edition among 373 adolescents living near a Superfund site in New Bedford, Massachusetts. We used Bayesian Kernel Machine Regression (BKMR) and linear regression analyses and assessed effect modification by sex and prenatal social disadvantage. In BKMR models, we observed an adverse joint association of the chemical mixture with Verbal, but not Symbolic, Working Memory. In co-exposure and covariate-adjusted linear regression models, a twofold increase in cord blood manganese was associated with lower working memory scaled scores, with a stronger association with Verbal Working Memory (difference = -0.75; 95% CI: -1.29, -0.20 points) compared to Symbolic Working Memory (difference = -0.44; 95% CI: -1.00, 0.12 points). There was little evidence of effect modification by sex and some evidence associating organochlorine pesticides with poorer working memory scores among those with greater prenatal social disadvantage. This study provided evidence of an adverse joint association of a chemical mixture with a verbal working memory task among adolescents, as well as an adverse association of prenatal manganese exposure with working memory., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Anesthetic agents disrupt neurodevelopment in animal models, but evidence in humans is mixed. The morphologic and behavioral changes observed across many species predicted that deficits should be seen in humans, but identifying a phenotype of injury in children has been challenging. It is increasingly clear that in children, a brief or single early anesthetic exposure is not associated with deficits in a range of neurodevelopmental outcomes including broad measures of intelligence. Deficits in other domains including behavior, however, are more consistently reported in humans and also reflect findings from nonhuman primates. The possibility that behavioral deficits are a phenotype, as well as the entire concept of anesthetic neurotoxicity in children, remains a source of intense debate. The purpose of this report is to describe consensus and disagreement among experts, summarize preclinical and clinical evidence, suggest pathways for future clinical research, and compare studies of anesthetic agents to other suspected neurotoxins., (Copyright © 2022, the American Society of Anesthesiologists. All Rights Reserved.)

Greater understanding of the pathways through which an environmental mixture operates is important to design effective interventions. We present new methodology to estimate natural direct and indirect effects and controlled direct effects of a complex mixture exposure on an outcome through a mediator variable. We implement Bayesian Kernel Machine Regression (BKMR) to allow for all possible interactions and nonlinear effects of (1) the co-exposures on the mediator, (2) the co-exposures and mediator on the outcome, and (3) selected covariates on the mediator and/or outcome. From the posterior predictive distributions of the mediator and outcome, we simulate counterfactuals to obtain posterior samples, estimates, and credible intervals of the mediation effects. Our simulation study demonstrates that when the exposure-mediator and exposure-mediator-outcome relationships are complex, BKMR-Causal Mediation Analysis performs better than current mediation methods. We applied our methodology to quantify the contribution of birth length as a mediator between in utero co-exposure to arsenic, manganese, and lead, and children's neurodevelopmental scores, in a prospective birth cohort in Bangladesh. Among younger children, we found a negative (adverse) association between the metal mixture and neurodevelopment. We also found evidence that birth length mediates the effect of exposure to the metal mixture on neurodevelopment for younger children. If birth length were fixed to its 75 t h percentile value, the harmful effect of the metal mixture on neurodevelopment is attenuated, suggesting nutritional interventions to help increase fetal growth, and thus birth length, could potentially block the harmful effect of the metal mixture on neurodevelopment., (© 2022 John Wiley & Sons Ltd.)

Gene-environment and nutrition-environment studies often involve testing of high-dimensional interactions between two sets of variables, each having potentially complex nonlinear main effects on an outcome. Construction of a valid and powerful hypothesis test for such an interaction is challenging, due to the difficulty in constructing an efficient and unbiased estimator for the complex, nonlinear main effects. In this work we address this problem by proposing a Cross-validated Ensemble of Kernels (CVEK) that learns the space of appropriate functions for the main effects using a cross-validated ensemble approach. With a carefully chosen library of base kernels, CVEK flexibly estimates the form of the main-effect functions from the data, and encourages test power by guarding against over-fitting under the alternative. The method is motivated by a study on the interaction between metal exposures in utero and maternal nutrition on children's neurodevelopment in rural Bangladesh. The proposed tests identified evidence of an interaction between minerals and vitamins intake and arsenic and manganese exposures. Results suggest that the detrimental effects of these metals are most pronounced at low intake levels of the nutrients, suggesting nutritional interventions in pregnant women could mitigate the adverse impacts of in utero metal exposures on children's neurodevelopment.

Cognitive flexibility, the ability to smoothly adapt to changing circumstances, is a skill that is vital to higher-level executive functions such as problem-solving, planning, and reasoning. As it undergoes substantial development during adolescence, decrements in cognitive flexibility may not become apparent until this time. There is evidence that prenatal exposure to individual chemicals may adversely impact executive functions in children, but few studies have explored the association of co-exposure to multiple chemicals with cognitive flexibility specifically among adolescents. We investigated this association among a diverse group of adolescents living near a Superfund site in New Bedford, Massachusetts. Specifically, using Bayesian kernel machine regression (BKMR) and multivariable regression analyses, we investigated the association of biomarkers of prenatal exposure to organochlorines (DDE, HCB, PCBs) and metals (lead, manganese) with cognitive flexibility, measured with four subtests of the Delis-Kaplan Executive Function System. In BKMR models, we observed adverse joint associations of the chemical mixture with two of the four cognitive flexibility subtests. In covariate-adjusted linear regression models, a two-fold increase in cord blood Mn was associated with poorer performance on two of the subtests: Trail-Making (scaled score difference = -0.60; 95% CI: -1.16, -0.05 points) and Color-Word Interference (scaled score difference = -0.53; 95% CI: -1.08, 0.01 points). These adverse Mn-cognitive flexibility associations were supported by the results of the BKMR. There was little evidence of effect modification by sex and some evidence of effect modification by a measure of social disadvantage, particularly for the associations between HCB and cognitive flexibility. This study is among the first to provide evidence of an adverse association of prenatal exposure to a chemical mixture with cognitive flexibility in adolescence.

Context: People with CHD are at increased risk for executive functioning deficits. Meta-analyses of these measures in CHD patients compared to healthy controls have not been reported., Objective: To examine differences in executive functions in individuals with CHD compared to healthy controls., Data Sources: We performed a systematic review of publications from 1 January, 1986 to 15 June, 2020 indexed in PubMed, CINAHL, EMBASE, PsycInfo, Web of Science, and the Cochrane Library., Study Selection: Inclusion criteria were (1) studies containing at least one executive function measure; (2) participants were over the age of three., Data Extraction: Data extraction and quality assessment were performed independently by two authors. We used a shifting unit-of-analysis approach and pooled data using a random effects model., Results: The search yielded 61,217 results. Twenty-eight studies met criteria. A total of 7789 people with CHD were compared with 8187 healthy controls. We found the following standardised mean differences: -0.628 (-0.726, -0.531) for cognitive flexibility and set shifting, -0.469 (-0.606, -0.333) for inhibition, -0.369 (-0.466, -0.273) for working memory, -0.334 (-0.546, -0.121) for planning/problem solving, -0.361 (-0.576, -0.147) for summary measures, and -0.444 (-0.614, -0.274) for reporter-based measures (p < 0.001)., Limitations: Our analysis consisted of cross-sectional and observational studies. We could not quantify the effect of collinearity., Conclusions: Individuals with CHD appear to have at least moderate deficits in executive functions. Given the growing population of people with CHD, more attention should be devoted to identifying executive dysfunction in this vulnerable group.

Introduction: Understanding the neurodevelopmental effects of manganese (Mn) is complicated due to its essentiality for growth and development. While evidence exists for the harmful effects of excess Mn, pediatric epidemiologic studies have observed inconsistent associations between Mn and child cognition., Objective: We sought to estimate prospective associations between Mn measured in three different early-life time windows with adolescent cognition using deciduous teeth biomarkers., Methods: Deciduous teeth were collected from 195 participants (ages 10-14 years) of the Public Health Impact of Manganese Exposure (PHIME) study in Brescia, Italy. Measurements of tooth Mn represented prenatal (∼14 weeks gestation - birth), early postnatal (birth - 1.5 years) and childhood (∼1.5 - 6 years) time windows. Neuropsychologists administered the Wechsler Intelligence Scale for Children, 3rd edition (WISC-III), to obtain composite IQ and subtest scores. Associations between tooth Mn at each time window and adolescent WISC-III scores were estimated using multivariable linear regression. We tested differences in associations between Mn and outcomes across time windows using multiple informant models. Sex-specific associations were explored in stratified models., Results: Adjusted associations between tooth Mn and composite IQ scores were positive in the prenatal period and negative in the childhood period. Associations were strongest for subtest scores that reflect working memory, problem solving, visuospatial ability and attention: prenatal Mn was positively associated with Digits backward [SD change in score per interquartile range increase in Mn: β = 0.20 (95 % CI: 0.02, 0.38)] and Block design [β = 0.21 (0.01, 0.41)] and early postnatal Mn was positively associated with Digits forward [β = 0.24 (0.09, 0.40)], while childhood Mn was negatively associated with Coding [β = -0.14 (-0.28, -0.001)]. Sex-stratified analyses suggested different Mn-cognition associations for boys and girls and was also dependent on the time window of exposure., Conclusion: Our results suggest that exposure timing is critical when evaluating Mn associations between Mn and cognition. Higher prenatal Mn was beneficial for adolescent cognition; however, these beneficial associations shifted towards harmful effects in later time windows. Cognitive domains most sensitive to Mn across time windows included visuospatial ability, working memory, attention and problem-solving., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Inhibition, one of the building blocks of executive function, is the ability to focus one's attention despite interference from external stimuli. It undergoes substantial development during adolescence and may be susceptible to adverse impacts of prenatal exposure to chemical mixtures, yet few studies have explored this association. The New Bedford Cohort (NBC) is a birth cohort of residents living near the New Bedford Harbor Superfund site in Massachusetts. Among adolescents from the NBC, we investigated the association of biomarkers of prenatal exposure to organochlorines (DDE, HCB, PCBs) and metals (Pb, Mn) with inhibition, assessed with the Delis-Kaplan Executive Function System Design Fluency (non-verbal task) and Color-Word Interference (verbal task) subtests. An exploratory mixtures analysis using Bayesian kernel machine regression (BKMR) informed a traditional multivariable regression approach. NBC adolescents are diverse with 29% non-white and 31% in a low-income household at birth. Cord serum organochlorine concentrations and cord blood metals concentrations were generally similar to other birth cohorts. In BKMR models, we observed a suggestive adverse association of the chemical mixture with Color-Word Interference but not Design Fluency. In covariate-adjusted linear regression models including all five chemical exposure measures, a doubling of cord blood Mn was associated with poorer Color-Word Interference completion time scaled scores (difference = -0.74; 95% CI: -1.34, -0.14). This study provided evidence of an adverse joint association between prenatal exposure to a five-chemical mixture and verbal inhibition in adolescence with exposure to Mn potentially driving this overall association.

Introduction: Prenatal exposure to fine particulate matter air pollution (PM2.5) is an important, under-studied risk factor for neurodevelopmental dysfunction. We describe the relationships between prenatal PM2.5 exposure and vigilance and inhibitory control, executive functions related to multiple health outcomes in Mexico City children., Methods: We studied 320 children enrolled in Programming Research in Obesity, GRowth, Environment and Social Stressors, a longitudinal birth cohort study in Mexico City. We used a spatio-temporal model to estimate daily prenatal PM2.5 exposure at each participant's residential address. At age 9-10 years, children performed three Go/No-Go tasks, which measure vigilance and inhibitory control ability. We used Latent class analysis (LCA) to classify performance into subgroups that reflected neurocognitive performance and applied multivariate regression and distributed lag regression modeling (DLM) to test overall and time-dependent associations between prenatal PM2.5 exposure and Go/No-Go performance., Results: LCA detected two Go/No-Go phenotypes: high performers (Class 1) and low performers (Class 2). Predicting odds of Class 1 vs Class 2 membership based on prenatal PM2.5 exposure timing, logistic regression modeling showed that average prenatal PM2.5 exposure in the second and third trimesters correlated with increased odds of membership in low-performance Class 2 (OR = 1.59 (1.16, 2.17), p = 0.004). Additionally, DLM analysis identified a critical window consisting of gestational days 103-268 (second and third trimesters) in which prenatal PM2.5 exposure predicted poorer Go/No-Go performance., Discussion: Increased prenatal PM2.5 exposure predicted decreased vigilance and inhibitory control at age 9-10 years. These findings highlight the second and third trimesters of gestation as critical windows of PM2.5 exposure for the development of vigilance and inhibitory control in preadolescent children. Because childhood development of vigilance and inhibitory control informs behavior, academic performance, and self-regulation into adulthood, these results may help to describe the relationship of prenatal PM2.5 exposure to long-term health and psychosocial outcomes. The integrative methodology of this study also contributes to a shift towards more holistic analysis., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Early life exposure to per- and polyfluoroalkyl substances (PFAS) may adversely impact neurodevelopment, but epidemiological findings are inconsistent. In the Project Viva pre-birth cohort, we examined associations of prenatal and childhood PFAS plasma concentrations with parent and teacher assessments of children's behavior problems [Strengths and Difficulties Questionnaire (SDQ)] and executive function abilities [Behavior Rating Inventory of Executive Function (BRIEF)] at age 6-10 years (sample sizes 485-933). PFAS concentrations in pregnant Project Viva mothers (in 1999-2002) and children at ages 6-10 (in 2007-10) were similar to concentrations at similar time points in women and children in the nationally representative U.S. National Health and Nutrition Examination Survey. We observed no consistent associations of prenatal PFAS concentrations with behavior or executive function. Childhood concentrations of perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS), perfluorononanoate (PFNA) and perfluorodecanoate (PFDA) were associated with higher parent-rated SDQ Total Difficulties scores (mean = 6.7, standard deviation (SD) = 4.9), suggesting greater behavioral problems (top (Q4) versus bottom (Q1) quartile PFOA: 1.5, 95% confidence interval (CI): 0.3, 2.7; PFOS: 1.4, 95% CI: 0.3, 2.5; PFHxS: 1.2, 95% CI: 0.1, 2.3; PFNA: 1.2, 95% CI: 0.1, 2.2; PFDA: 1.1, 95% CI: 0.0, 1.1); teacher-rated SDQ scores did not show associations. Higher childhood PFOS was associated with higher (indicating more problems) parent-rated BRIEF General Executive Composite (GEC) scores (standardized to mean = 50, SD = 10) (Q4 vs. Q1: 2.4, 95% CI: 0.2, 4.6), while teacher BRIEF GEC scores indicated more problems among children with higher PFHxS (Q4 vs. Q1: 3.5, 95% CI: -0.8, 6.3). There were no consistent patterns of sexual dimorphism in associations. In a cohort of U.S. children, we observed cross-sectional associations of childhood PFAS concentrations with greater behavioral and executive function problems, but no consistent associations with prenatal PFAS., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Lead (Pb), manganese (Mn), selenium (Se) and methylmercury (MeHg) can be neurotoxic individually, despite Mn and Se also being essential elements. Little is known about the joint effects of essential and non-essential elements on neurobehavior, particularly for prenatal exposures., Objectives: To evaluate associations of prenatal exposure to multiple elements with executive function and neurobehavior in children., Methods: Participants included 1009 mother-child pairs from the Project Viva pre-birth cohort. We estimated maternal erythrocyte Pb, Mn, Se, and Hg concentrations prenatally. In 6-11-year old children (median 7.6 years), parents and teachers rated children's executive function-related behaviors using the Behavior Rating Inventory of Executive Function (BRIEF) Global Executive Composite score and behavioral difficulties using the Strengths and Difficulties Questionnaire (SDQ) total difficulties score. We evaluated associations of element mixtures with neurobehavior using Bayesian kernel machine regression (BKMR), multivariable linear regression, and quantile g-computation., Results: Median erythrocyte Pb, Mn, Se, and Hg concentrations were 1.1 μg/dL, 33.1 μg/L, 204.5 ng/mL, and 3.1 ng/g, respectively. Findings from BKMR and quantile g-computation models both showed worse (higher) parent-rated BRIEF and SDQ z-scores with higher concentrations of the mixture, although estimates were imprecise. When remaining elements were set at their median within BKMR models, increases in Pb and Se from the 25th to 75th percentile of exposure distributions were associated with 0.08 (95% CI: 0.02, 0.19) and 0.07 (95% CI: 0.03, 0.16) standard deviation increases in parent-rated BRIEF scores, and 0.08 (95% CI: 0.02, 0.17) and 0.05 (95% CI: 0.03, 0.13) standard deviation increases in SDQ scores, respectively. There was no evidence of element interactions., Discussion: Although associations were small in magnitude, we found a trend of worsening neurobehavioral ratings with increasing prenatal exposure to an element mixture. However, we may be observing a limited range of dose-dependent impacts given the levels of exposure within our population., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: This study examined longitudinal associations between performance on the Rey-Osterrieth Complex Figure-Developmental Scoring System (ROCF-DSS) at 8 years of age and academic outcomes at 16 years of age in 133 children with dextro-transposition of the great arteries (d-TGA)., Method: The ROCF-DSS was administered at the age of 8 and the Wechsler Individual Achievement Test, First and Second Edition (WIAT/WIAT-II) at the ages of 8 and 16, respectively. ROCF-DSS protocols were classified by Organization (Organized/Disorganized) and Style (Part-oriented/Holistic). Two-way univariate (ROCF-DSS Organization × Style) ANCOVAs were computed with 16-year academic outcomes as the dependent variables and socioeconomic status (SES) as the covariate., Results: The Organization × Style interaction was not statistically significant. However, ROCF-DSS Organization at 8 years was significantly associated with Reading, Math, Associative, and Assembled academic skills at 16 years, with better organization predicting better academic performance., Conclusions: Performance on the ROCF-DSS, a complex visual-spatial problem-solving task, in children with d-TGA can forecast academic performance in both reading and mathematics nearly a decade later. These findings may have implications for identifying risk in children with other medical and neurodevelopmental disorders affecting brain development.

Background: Africa is undergoing both an environmental and an epidemiological transition. Household air pollution is the predominant form of air pollution, but it is declining, whereas ambient air pollution is increasing. We aimed to quantify how air pollution is affecting health, human capital, and the economy across Africa, with a particular focus on Ethiopia, Ghana, and Rwanda., Methods: Data on household and ambient air pollution were from WHO Global Health Observatory, and data on morbidity and mortality were from the 2019 Global Burden of Disease Study. We estimated economic output lost due to air pollution-related disease by country, with use of labour income per worker, adjusted by the probability that a person (of a given age) was working. Losses were expressed in 2019 international dollars and as a proportion of gross domestic product (GDP). We also quantified the contribution of particulate matter (PM) 2·5 pollution to intelligence quotient (IQ) loss in children younger than 10 years, with use of an exposure-response coefficient based on previously published data., Findings: Air pollution was responsible for 1·1 million deaths across Africa in 2019. Household air pollution accounted for 697 000 deaths and ambient air pollution for 394 000. Ambient air pollution-related deaths increased from 361 000 in 2015, to 383 000 in 2019, with the greatest increases in the most highly developed countries. The majority of deaths due to ambient air pollution are caused by non-communicable diseases. The loss in economic output in 2019 due to air pollution-related morbidity and mortality was $3·02 billion in Ethiopia (1·16% of GDP), $1·63 billion in Ghana (0·95% of GDP), and $349 million in Rwanda (1·19% of GDP). PM 2·5 pollution was estimated to be responsible for 1·96 billion lost IQ points in African children in 2019., Interpretation: Ambient air pollution is increasing across Africa. In the absence of deliberate intervention, it will increase morbidity and mortality, diminish economic productivity, impair human capital formation, and undercut development. Because most African countries are still early in development, they have opportunities to transition rapidly to wind and solar energy, avoiding a reliance on fossil fuel-based economies and minimising pollution., Funding: UN Environment Programme., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Neurodevelopmental disabilities are the most common noncardiac conditions in patients with congenital heart disease (CHD). Executive function skills have been frequently observed to be decreased among children and adults with CHD compared with peers, but a neuroanatomical basis for the association is yet to be identified. In this study, we quantified sulcal pattern features from brain magnetic resonance imaging data obtained during adolescence among 41 participants with tetralogy of Fallot (ToF) and 49 control participants using a graph-based pattern analysis technique. Among patients with ToF, right-hemispheric sulcal pattern similarity to the control group was decreased (0.7514 vs. 0.7553, P = 0.01) and positively correlated with neuropsychological testing values including executive function (r = 0.48, P < 0.001). Together these findings suggest that sulcal pattern analysis may be a useful marker of neurodevelopmental risk in patients with CHD. Further studies may elucidate the mechanisms leading to different alterations in sulcal patterning., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Developmental exposure to particulate matter (PM) air pollution may impair children's behaviors. Our objectives were to quantify the impact of reducing indoor PM using portable HEPA filter air cleaners during pregnancy on behavioral problems in children and to assess associations between indoor fine PM (PM 2.5 ) concentrations during pregnancy and children's behavior., Methods: This is a secondary analysis of a single-blind parallel-group randomized controlled trial in which we randomly assigned 540 non-smoking pregnant women to receive 1 or 2 HEPA filter air cleaners or no air cleaners. We administered the Behavior Assessment System for Children (BASC-3) to caregivers when children were a mean age of 23 months, and again at a mean age of 48 months. Primary outcomes were the four BASC-3 composite scales: externalizing problems, internalizing problems, adaptive skills, and the behavioral symptoms index. We imputed missing data using multiple imputation with chained equations. The primary analysis was by intention-to-treat. In a secondary analysis, we evaluated associations between BASC-3 composite indices and modeled trimester-specific PM 2.5 concentrations inside residences., Results: We enrolled participants at a median of 11 weeks gestation. After excluding miscarriages, still births and neonatal deaths, our analysis included 478 children (233 control and 245 intervention). We observed no differences in the mean BASC-3 scores between treatment groups. An interquartile increase (20.1 µg/m 3 ) in first trimester PM 2.5 concentration was associated with higher externalizing problem scores (2.4 units, 95% CI: 0.7, 4.1), higher internalizing problem scores (2.4 units, 95% CI: 0.7, 4.0), lower adaptive skills scores (-1.5 units, 95% CI: -3.0, 0.0), and higher behavior symptoms index scores (2.3 units, 95% CI: 0.7, 3.9). Third trimester PM 2.5 concentrations were also associated with some behavioral indices at age 4, but effect estimates were smaller. No significant associations were observed with PM 2.5 concentrations during the second trimester or for any of the BASC indices when children were 2 years old., Conclusion: We found no benefit of reducing indoor particulate air pollution during pregnancy on parent-reported behaviors in children. Associations between indoor PM 2.5 concentrations in the first trimester and behavioral scores among 4-year old children suggest that it may be necessary to intervene early in pregnancy to protect children, but these exploratory findings should be interpreted cautiously., Trial Registration: ClinicalTrials.gov: NCT01741051.

Competing Interests: Competing interests: None declared.

Background: Many children in Bangladesh experience poor nutritional status and environmental lead exposure, both of which are associated with lower scores on neurodevelopmental assessments. Recent studies have suggested that part of lead's adverse effects on neurodevelopment are caused in part by lead's effect on growth. New statistical methods are now available to evaluate potential causal pathways in observational studies. This study used a novel statistical method to test the hypothesis that stunting, a measure of linear growth related to poor nutrition, is a mediator and/or an effect modifier of the lead exposure's adverse effect on cognitive development., Methods: Participants were 734 children from a longitudinal birth cohort established in rural Bangladesh to study the health effects of prenatal and early childhood environmental metal exposures. Lead exposure was estimated using umbilical cord blood samples obtained at birth and blood obtained via venipuncture at age 20-40 months. Stunting was determined using the World Health Organization's standards. Neurodevelopment was assessed at age 20-40 months years using the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III). We evaluated the effect of lead on stunting and whether the effect of lead on cognitive scores is modified by stunting status in multivariable regression analyses. We then conducted a novel 4-way mediation analysis that allows for exposure-mediator interaction to assess how much of the effect of lead on cognitive scores is explained by the pathway through stunting (mediation) and how much is explained by the interaction between lead and stunt (effect modification)., Results: Stunting was not a mediator of the effect of lead in our analyses. Results suggested effect modification by stunting. In an area of Bangladesh with lower lead exposures (median umbilical cord blood lead concentration, 1.7 μg/dL), stunting modified the relationship between prenatal blood lead concentrations and cognitive score at age 2-3 years. A 1-unit increase in natural log cord blood lead concentration in the presence of stunting was associated with a 2.1-unit decrease in cognitive scores (β = - 2.10, SE = 0.71, P = 0.003). This interaction was not found in a second study site where lead exposures were higher (median umbilical cord blood lead concentration, 6.1 μg/dL, β = - 0.45, SE = 0.49, P = 0.360)., Conclusions: We used a novel method of mediation analysis to test whether stunting mediated the adverse effect of prenatal lead exposure on cognitive outcomes in Bangladesh. While we did not find that stunting acted as mediator of lead's effect on cognitive development, we found significant effect modification by stunting. Our results suggest that children with stunting are more vulnerable to the adverse effects of low-level lead exposure.

Objectives: To evaluate the efficacy of Cogmed Working Memory Training compared with the standard of care to improve executive function and social outcomes in adolescents with congenital heart disease (CHD) who underwent open-heart surgery in infancy and to identify factors associated with changes in outcomes following the intervention., Study Design: In a single-center, randomized controlled trial, adolescents (13-16 years) with CHD were randomly assigned to either Cogmed (home-based 45-minutes sessions for 5-8 weeks) or to a control group. The primary outcome was working memory. Secondary outcomes included inhibitory control and cognitive flexibility as well as parent-reported executive function, symptoms of attention deficit hyperactivity disorder, and social outcomes. All measures were assessed at baseline, post-treatment (1-3 weeks post-training) and at 3-month follow-up. Data were analyzed using an intention-to-treat approach., Results: Sixty adolescents with CHD participated (28 assigned to Cogmed). No improvement at the post-treatment or 3-month follow-up assessments was found for the primary outcome measure of working memory. Compared with the control group, participants assigned to the intervention demonstrated benefits in inhibitory control and attention at the 3-month follow-up (P = .02) and in parent-reported cognitive regulatory skills at post-treatment and 3-month follow-up (P = .02 and P = .04, respectively). Preterm birth, biventricular CHD, and history of attention deficit hyperactivity disorder diagnosis were associated with improved response to the intervention., Conclusions: Cogmed intervention produced improvements in the self-regulatory control abilities of adolescents with CHD. The training did not enhance other areas of executive function or behavioral outcomes. Further studies are needed to evaluate the longer-term potential benefits to other domains., Trial Registration: Clinicaltrials.gov: NCT02759263., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Childhood exposure to air pollution has been linked with maladaptive cognitive development; however, less is known about the association between prenatal fine particulate matter (PM 2.5 ) exposure and childhood behavior., Objectives: Our aim was to assess the association between prenatal PM 2.5 exposure and behavioral development in 4-6 year old children residing in Mexico City., Methods: We used data from 539 mother-child pairs enrolled in a prospective birth cohort in Mexico City. We estimated daily PM 2.5 exposure using a 1 km 2 satellite-based exposure model and averaged over each trimester of pregnancy. We assessed childhood behavior at 4-6 years of age using the parent-completed Behavioral Assessment Scale for Children (BASC-2) composite scores and subscales. We used linear regression models to estimate change in BASC-2 T-scores with trimester specific 5-μg/m 3 increases in PM 2.5 . All models were mutually adjusted for PM 2.5 exposures during the other trimesters, maternal factors including age, education, socioeconomic status, depression, and IQ, child's age at study visit, and season. We additionally assessed sex-specific effects by including an interaction term between PM 2.5 and sex., Results: Higher first trimester PM 2.5 exposure was associated with reduced Adaptive Skills scores (β: -1.45, 95% CI: -2.60, -0.30). Lower scores on the Adaptive Skills composite score and subscales indicate poorer functioning. For PM 2.5 exposure during the first trimester, decrements were consistent across adaptive subscale scores including Adaptability (β: -1.51, 95% CI: -2.72, -0.30), Social Skills (β: -1.63, 95% CI: -2.90, -0.36), and Functional Communication (β: -1.21, 95% CI: -2.21, -0.21). The association between 1 st trimester PM 2.5 and depression was stronger in males than females (β for males: 1.52, 95% CI: -0.41, 3.45; β for females: -0.13, 95% CI: -1.99, 1.72; p-int: 0.07)., Conclusions: Exposure to PM 2.5 during early pregnancy may be associated with impaired behavioral development in children, particularly for measures of adaptive skills. These results suggest that air pollution impacts behavioral domains as well as cognition, and that the timing of exposure may be critical., (Copyright © 2020. Published by Elsevier B.V.)

In 2012, the American Heart Association and the American Academy of Paediatrics released a scientific statement with guidelines for the evaluation and management of the neurodevelopmental needs of children with CHD. Decades of outcome research now highlight a range of cognitive, learning, motor, and psychosocial vulnerabilities affecting individuals with CHD across the lifespan. The number of institutions with Cardiac Neurodevelopmental Follow-Up Programmes and services for CHD is growing worldwide. This manuscript provides an expanded set of neurodevelopmental evaluation strategies and considerations for professionals working with school-age children with CHD. Recommendations begin with the referral process and access to the evaluation, the importance of considering medical risk factors (e.g., genetic disorders, neuroimaging), and the initial clinical interview with the family. The neurodevelopmental evaluation should take into account both family and patient factors, including the child/family's primary language, country of origin, and other cultural factors, as well as critical stages in development that place the child at higher risk. Domains of assessment are reviewed with emphasis on target areas in need of evaluation based on current outcome research with CHD. Finally, current recommendations are made for assessment batteries using a brief core battery and an extended comprehensive clinical battery. Consistent use of a recommended assessment battery will increase opportunities for research collaborations, and ultimately help improve the quality of care for families and children with CHD.

It is believed that genetic factors play a large role in the development of many cognitive and neurological processes; however, epidemiological evidence for the genetic basis of childhood neurodevelopment is very limited. Identification of the genetic polymorphisms associated with early-stage neurodevelopment will help elucidate biological mechanisms involved in neuro-behavior and provide a better understanding of the developing brain. To search for such variants, we performed a genome-wide association study (GWAS) for infant mental and motor ability at two years of age with mothers and children recruited from cohorts in Bangladesh and Mexico. Infant ability was assessed using mental and motor composite scores calculated with country-specific versions of the Bayley Scales of Infant Development. A missense variant (rs1055153) located in the gene WWTR1 reached genome-wide significance in association with mental composite score (meta-analysis effect size of minor allele β meta  = -6.04; 95% CI: -8.13 to -3.94; P = 1.56×10 -8 ). Infants carrying the minor allele reported substantially lower cognitive scores in both cohorts, and this variant is predicted to be in the top 0.3% of most deleterious substitutions in the human genome. Fine mapping and region-based association testing provided additional suggestive evidence that both WWTR1 and a second gene, LRP1B, were associated with infant cognitive ability. Comparisons with recently conducted GWAS in intelligence and educational attainment indicate that our phenotypes do not possess a high genetic correlation with either adolescent or adult cognitive traits, suggesting that infant neurological assessments should be treated as an independent outcome of interest. Additional functional studies and replication efforts in other cohorts may help uncover new biological pathways and genetic architectures that are crucial to the developing brain.

Background: Prevalence of antenatal depression in low and middle income countries is high. However studies examining the association between maternal antenatal depression and early childhood development from these countries are scarce. The objective of the study was to examine the association between antenatal depressive symptoms assessed serially during pregnancy and child neurodevelopment outcomes in mother-child dyads part of a randomized control trial of maternal B12 supplementation during pregnancy., Method: Subjects were 203 women who had participated in the placebo-controlled, randomized trial of vitamin B12 supplementation during pregnancy and 6 weeks post-partum on whom serial assessments of depressive symptoms in each of the trimesters were available. Cognitive, receptive language, expressive language, fine motor skills and gross motor skills were assessed at 30 months using the Bayley's Scale of Infant Development-3rd edition (BSID-III). Antenatal depressive symptoms were assessed at three trimesters using the Kessler's 10 Psychological Distress Scale (K10). Women were classified into three categories: not depressed (K10 <6 in all trimesters), with intermittent depressive symptoms (K10 ≥6 in at least one trimester) and with persistent depressive symptoms (K10 score ≥6 in at least 2 trimesters)., Results: 112 (55.2%) of the women did not have depressive symptoms, 58 (28.6%) had intermittent depressive symptoms and 33 (16.2%) had persistent depressive symptoms. The children of women with intermittent antenatal depressive symptoms scored lower on the receptive language domain on BSID-III compared to children of women who were not depressed on univariate analysis, but not on bivariate regression analysis. Women with persistent depressive symptoms had lower educational attainment (p = 0.004), lower social support (p = 0.006) and used more emotional coping strategies (p = 0.005) compared to the not depressed group., Conclusions: A significant number of women in south India had antenatal depressive symptoms. Findings from this study suggest a possible association between antenatal depressive symptoms and receptive language in children. Larger studies including women with clinical depression are needed to confirm these findings., (Copyright © 2020 Thomas, Vigil, Thomas, Bellinger, Ramthal, Kurpad, Duggan and Srinivasan.)

Importance: Attention-deficit/hyperactivity disorder (ADHD) is the most common childhood neurobehavioral disorder. Studies suggest that prenatal and early childhood exposure to endocrine-disrupting chemicals may be associated with ADHD, but the association during adolescence has not been studied to date., Objective: To evaluate the association between exposure to select endocrine-disrupting chemicals during adolescence and ADHD-related behaviors., Design, Setting, and Participants: For this cross-sectional analysis, data were collected from 205 adolescents in the New Bedford Cohort, an ongoing prospective birth cohort, between June 18, 2011, and June 10, 2014. The adolescents provided spot urine samples and underwent neurodevelopmental testing. Statistical analyses performed from January 15 to December 31, 2019, used a repeated-measures analysis with multivariate modified Poisson models to estimate the adjusted relative risk of ADHD-related behaviors associated with exposure to endocrine-disrupting chemicals., Exposures: Urinary biomarker concentrations of endocrine-disrupting chemicals or their metabolites, including phthalates, parabens, phenols, and triclocarban, were quantified. Summary exposure measures were created, combining biomarker concentrations of chemicals with a shared mechanism of action, exposure pathway, or chemical class., Main Outcomes and Measures: Behaviors related to ADHD were assessed with up to 14 indices from self-, parent-, and teacher-completed behavioral checklists using validated and standardized instruments; specifically, the Conners Attention Deficit Scale and the Behavior Assessment System for Children, Second Edition. Scores on each index were dichotomized to identify those with evidence of a significant behavioral problem, defined by each scale's interpretive guidelines., Results: Among the 205 participants, the mean (SD) age at assessment was 15.3 (0.7) years, with 112 girls (55%) and 124 non-Hispanic White participants (61%). The median urine concentrations were 0.45 μmol/L of Σantiandrogenic phthalates, 0.13 μmol/L of ΣDEHP metabolites, 0.49 μmol/L of Σpersonal care product phthalates, 0.35 μmol/L of Σparabens, 0.02 μmol/L of Σbisphenols, and 0.02 μmol/L of Σdichlorophenols. A total of 82 (40%) had scores consistent with a significant behavioral problem, whereas 39 (19%) had an ADHD diagnosis. Each 2-fold increase in the sum of antiandrogenic phthalate concentrations was associated with a 1.34 (95% CI, 1.00-1.79) increase in the risk of significant ADHD-related behavior problems, whereas a 2-fold increase in the sum of dichlorophenols was associated with a 1.15 (95% CI, 1.01-1.32) increased risk. These associations tended to be stronger in male participants, but comparisons of sex-specific differences were imprecise., Conclusions and Relevance: Endocrine-disrupting chemicals are used in a wide variety of consumer products resulting in ubiquitous exposure. The study findings suggest that exposure to some of these chemicals, particularly certain phthalates, during adolescence may be associated with behaviors characteristic of ADHD.

Background: We evaluated: (1) associations of prenatal manganese (Mn) levels with child neurodevelopment at 4-6 years; (2) effect modification by maternal anemia and iron deficiency; and (3) sex-specific effects., Methods: We measured blood Mn, hemoglobin, and serum ferritin in mothers at the second trimester, third trimester, and at birth, and in cord blood from a prospective birth cohort in Mexico City (n = 571). McCarthy Scales of Children's Abilities were measured at 4-6 years. Using linear regression, we estimated associations between prenatal Mn and neurodevelopment, examined anemia and iron deficiency as effect modifiers, and analyzed associations by child sex., Results: No direct associations were observed between Mn, anemia, or iron deficiency and McCarthy Scales. Second trimester iron deficiency and third trimester anemia modified the effect of Mn on child neurodevelopment. For instance, second trimester Mn was positively associated child memory scores in mother's with normal ferritin (1.85 (0.02, 3.45)), but negatively associated in mother's with low ferritin (-2.41 (-5.28, 0.47), interaction P value = 0.01), a pattern observed across scales. No effect modification at birth or in cord blood was observed., Conclusions: Anemia/iron deficiency during pregnancy may modify Mn impacts on child neurodevelopment, particularly in boys.

Neurodevelopmental abnormalities are the most common noncardiac complications in patients with congenital heart disease (CHD). Prenatal brain abnormalities may be due to reduced oxygenation, genetic factors, or less commonly, teratogens. Understanding the contribution of these factors is essential to improve outcomes. Because primary sulcal patterns are prenatally determined and under strong genetic control, we hypothesized that they are influenced by genetic variants in CHD. In this study, we reveal significant alterations in sulcal patterns among subjects with single ventricle CHD (n = 115, 14.7 ± 2.9 years [mean ± standard deviation]) compared with controls (n = 45, 15.5 ± 2.4 years) using a graph-based pattern-analysis technique. Among patients with CHD, the left hemisphere demonstrated decreased sulcal pattern similarity to controls in the left temporal and parietal lobes, as well as the bilateral frontal lobes. Temporal and parietal lobes demonstrated an abnormally asymmetric left-right pattern of sulcal basin area in CHD subjects. Sulcal pattern similarity to control was positively correlated with working memory, processing speed, and executive function. Exome analysis identified damaging de novo variants only in CHD subjects with more atypical sulcal patterns. Together, these findings suggest that sulcal pattern analysis may be useful in characterizing genetically influenced, atypical early brain development and neurodevelopmental risk in subjects with CHD., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)